Many drugs inhibit the human
ether-a-go-go-related gene (HERG) cardiac K+ channel. This leads to action potential prolongation on the cellular level, a prolongation of the QT interval on the electrocardiogram, and sometimes
cardiac arrhythmia. To date, no activators of this channel have been reported. Here, we describe the in vitro electrophysiological effects of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-
piperidine-3-
carboxylic acid (
RPR260243), a novel activator of HERG. Using patch-clamp electrophysiology, we found that
RPR260243 dramatically slowed current deactivation when applied to cells stably expressing HERG. The effects of
RPR260243 on HERG channel deactivation were temperature- and voltage-dependent and occurred over the concentration range of 1 to 30 microM. RPR260243-modified HERG currents were inhibited by
dofetilide (IC50 = 58 nM).
RPR260243 had little effect on HERG current amplitude and no significant effects on steady-state activation parameters or on channel inactivation processes.
RPR260243 displayed no activator-like effects on other voltage-dependent
ion channels, including the closely related erg3 K+ channel.
RPR260243 enhanced the delayed rectifier current in guinea pig myocytes but, when administered alone, had little effect on action potential parameters in these cells. However,
RPR260243 completely reversed the action potential-prolonging effects of
dofetilide in this preparation. Using the Langendorff heart method, we found that 5 microM
RPR260243 increased T-wave amplitude, prolonged the PR interval, and shortened the QT interval. We believe
RPR260243 represents the first known HERG channel activator and that the
drug works primarily by inhibiting channel closure, leading to a persistent HERG channel current upon repolarization. Compounds like
RPR260243 will be useful for studying the physiological role of HERG and may one day find use in treating
cardiac disease.